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Evaluating the association of single-nucleotide polymorphisms with tenofovir exposure in a diverse prospective cohort of women living with HIV

The Pharmacogenomics Journal volume 18, pages 245–250 (2018)Cite this article

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Abstract

Higher exposure to tenofovir (TFV) increases the risk for kidney function decline, but the impact of genetic factors on TFV exposure is largely unknown. We investigated whether single-nucleotide polymorphisms (SNPs, n=211) in 12 genes are potentially involved in TFV exposure. Participants (n=91) from the Women’s Interagency HIV Study, underwent a 24 h intensive pharmacokinetic sampling of TFV after witnessed dose and TFV area under the time–concentration curves (AUCs) were calculated for each participant. SNPs were assayed using a combination of array genotyping and Sanger sequencing. Linear regression models were applied to logarithmically transformed AUC. Those SNPs that met an a priori threshold of P<0.001 were considered statistically associated with TFV AUC. ABCG2 SNP rs2231142 was associated with TFV AUC with rare allele carriers displaying 1.51-fold increase in TFV AUC (95% confidence interval: 1.26, 1.81; P=1.7 × 10−5). We present evidence of a moderately strong effect of the rs2231142 SNP in ABCG2 on a 24 h TFV AUC.

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Acknowledgements

We thank the Women's Interagency HIV Study (WIHS) participants who contributed data to this study. Data were collected by the WIHS Collaborative Study Group with centers (Principal Investigators at the time of data collection) at New York City/Bronx Consortium (KA); Brooklyn, New York (Howard Minkoff, MD); Washington DC, Metropolitan Consortium (MAY); The Connie Wofsy Study Consortium of Northern California (RMG, Phyllis Tien and BEA); Los Angeles County/Southern California Consortium (Alexandra Levine, MD); Chicago Consortium (MC); and Data Coordinating Center (SJG). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the US National Institutes of Health. WIHS (Principal Investigators): UAB-MS WIHS (Michael Saag, Mirjam-Colette Kempf and Deborah Konkle-Parker), U01-AI-103401; Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood), U01-AI-103408; Bronx WIHS (KA), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (MC and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (MAY and Seble Kassaye), U01-AI-034994; Miami WIHS (Margaret Fischl and Lisa Metsch), U01-AI-103397; UNC WIHS (Adaora Adimora), U01-AI-103390; Connie Wofsy Women’s HIV Study, Northern California (RMG, BEA and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (SJG and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I – WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA) and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD) and the NIH Office of Research on Women’s Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA). SMB is supported by the UCSF Traineeship in AIDS Prevention Studies (US National Institutes of Health (NIH) T32 MH-19105). This research was also supported by a grant from the National Institutes of Health, University of California, San Francisco-Gladstone Institute of Virology and Immunology Center for AIDS Research, P30-AI027763.

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Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    S M Baxi & R M Greenblatt

  2. School of Public Health, University of California, Berkeley, Berkeley, CA, USA

    S M Baxi

  3. Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, CA, USA

    R M Greenblatt & B E Aouizerat

  4. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA

    R M Greenblatt & P Bacchetti

  5. Division of Infectious Diseases, CORE Center, John H. Stroger Jr. Hospital of Cook County, Chicago, IL, USA

    M Cohen

  6. Division of Infectious Diseases, State University of New York, Downstate Medical Center, Brooklyn, NY, USA

    J A DeHovitz

  7. Departments of Medicine and Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY, USA

    K Anastos

  8. Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    S J Gange

  9. Department of Medicine, Georgetown University Medical Center, Washington, DC, USA

    M A Young

  10. Bluestone Center for Clinical Research, College of Dentistry, New York University, New York, NY, USA

    B E Aouizerat

  11. Department of Oral and Maxillofacial Surgery, College of Dentistry, New York University, New York, NY, USA

    B E Aouizerat

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Results from this paper were presented, in part, at the 22nd Conference on Retroviruses and Opportunistic Infections in Seattle, WA, USA, from 23–26 February 2015.

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Baxi, S., Greenblatt, R., Bacchetti, P. et al. Evaluating the association of single-nucleotide polymorphisms with tenofovir exposure in a diverse prospective cohort of women living with HIV. Pharmacogenomics J 18, 245–250 (2018). https://doi.org/10.1038/tpj.2017.3

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